The founders of Marval Therapeutics have invented a new class of liposomal nanoparticle contrast agents for Computed Tomography (CT), referred to as NCTX. In our Phase 1 application, we sought funding to support a key development step for this class of agents: to achieve a sufficiently high iodine concentration for the purpose of enabling CT imaging in humans with reasonable injection volumes. In this Phase 2 proposal, we seek rapid translation to clinical use of the NCTX platform by studying the ability of NCTX to simultaneously image all regions of the thoracic vasculature (right heart/pulmonary, left heart/aorta and coronary vasculature) using the 3RO procedure. First, we will compare the ability of NCTX (relative to conventional contrast agents) to image thoracic vasculature in a large animal model (sheep). Second, we will acquire key pharmacokinetics (PK) and toxicity data required to justify the use of NCTX in humans. While the organ distribution of the liposomes used in NCTX is well understood, our conversations with Venture Capital organizations interested in funding Phase 3 have indicated that these are the 2 key pieces of information required before they would provide Phase 3 funding. The Specific Aims of this Phase 2 application are: 1. Test Detection by NCTX: To compare the detection of (1) catheter-placed pulmonary emboli and (2) artificial coronary artery stenoses by conventional contrast-enhanced CT and NCTX. Specifically, the number of contrast doses and the X-ray dose required for each method will be investigated. Organ distribution of the agents will be measured by CT imaging. 2. Preliminary Toxicity Testing: The filing of an IND (Investigational New Drug) application with the FDA for NCTX will require toxicity and PK testing in one small animal and one large animal model. Mice and Dogs are usually recommended for such testing. In this study, we will study the toxicity in mice. The elimination route, renal toxicity, and hepatic toxicity of the NCTX agent will be studied, and compared to that of conventional contrast agent. The founders of Marval Therapeutics have invented a new class of liposomal nanoparticle contrast agents for Computed Tomography (CT), referred to as NCTX. In our Phase 1 application, we sought funding to support a key development step for this class of agents: to achieve a sufficiently high iodine concentration for the purpose of enabling CT imaging in humans with reasonable injection volumes. Subsequent to successful realization of this technical advance, the sole Specific Aim of the Phase 1 application, we have pursued translational research focused on development of clinical applications for the use of NCTX. While several clinically significant applications were identified, we focused on one particularly compelling indication that is not effectively addressed by current imaging technology: acute chest pain -- a condition that causes 5-8 million patients to present to Emergency Rooms (ER's) every year in the US alone. From a clinical perspective, there are three distinct, life-threatening causes of acute chest pain: pulmonary embolus (PE), myocardial infarction due to coronary insufficiency (MI) and dissecting aortic aneurysm (AD). The diagnosis (or exclusion) of these three entities is complex and frequently requires admission to the hospital and highly invasive testing; however, it has recently been proposed that these 3 entities can be diagnosed non-invasively in the ER using the latest generation of ultrafast, 64-slice multi- detector CT scanners. Even with the latest scanner technology, this "triple rule-out" (3RO) procedure is currently very difficult to perform due to the need to accurately image the pulmonary, coronary and aortic circulations, during peak enhancement. The 3RO is the subject of extensive research by both clinicians and scanner manufacturers. In this Phase 2 proposal, we seek rapid translation to clinical use of the NCTX platform by studying the ability of NCTX to simultaneously image all regions of the thoracic vasculature (right heart/pulmonary, left heart/aorta and coronary vasculature) using the 3RO procedure. First, we will compare the ability of NCTX (relative to conventional contrast agents) to image thoracic vasculature in a large animal model (sheep). Second, we will acquire key pharmacokinetics (PK) and toxicity data required to justify the use of NCTX in humans. While the organ distribution of the liposomes used in NCTX is well understood, our conversations with Venture Capital organizations interested in funding Phase 3 have indicated that these are the 2 key pieces of information required before they would provide Phase 3 funding. [unreadable] [unreadable] [unreadable]